JP2001220348A - Hypoglycemic comprising zinc (ii) organic complex - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hypoglycemic that has lower toxicity than vanadium, a suitable level of stability, a suitable level of lipophilicity and insulin-like action, insulin-like action and hypoglycemic action and is useful as a prophylaxis and a therapy for diabetes. SOLUTION: This hypoglycemic comprises a zinc (II) organic complex bearing pyridine ring-bearing ligand, pyrone ring-bearing ligand, thiazolidine ring-bearing ligand, amino acid ligand, or a ligand of 2-aminothiophenols, or a ligand of pyrrolidine thiocarbamate ligand (for example, trans-bis(picolinate)zinc (II) complex [Zn(PA)2(H2O)2] represented by formula 1) and a medicinal preparation that includes the zinc (II) organic complex.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a hypoglycemic agent comprising an organic zinc (II) complex. More specifically, the present invention relates to a ligand having a pyridine ring, a ligand having a pyrone ring, a ligand having a thiazolidine ring, a ligand having a thiophene ring, a ligand comprising amino acids, Zinc having a ligand comprising an aminothiophenol or a ligand comprising a dithiocarbamic acid as a ligand (I
I) It relates to a hypoglycemic agent comprising an organic complex. The present invention also relates to an oral administration preparation comprising a zinc (II) organic complex and having a hypoglycemic action and an insulin-like action.

[0002]

2. Description of the Related Art Despite dramatic advances in medical technology,
In Japan, various adult diseases such as Alzheimer's disease, ischemic heart disease, and diabetes have become major problems. Among them, diabetes is a disease with many potential patients, and the number continues to increase every year. Currently, diabetes is caused by glucose or protein metabolism due to the absolute or relative lack of insulin.
It is defined as a disorder that causes abnormalities in lipid metabolism and further results in chronic diabetic complications such as nephropathy, retinopathy, and neurosis as a result of chronic hyperglycemia. And then,
The World Health Organization (WHO) classifies diabetes into type I (insulin-dependent) diabetes and type II (non-insulin-dependent) diabetes. The pathology of type I diabetes is due to an absolute deficiency of insulin, in which B cells in the pancreas are destroyed by autoimmune insulitis and insulin is not synthesized or secreted at all. Therefore, at present, the only alternative is to rely on insulin injection, and a therapeutic agent that can replace insulin is desired. On the other hand, the pathology of type II diabetes is due to the relative shortage of insulin, which is caused by impaired insulin secretion and action. Factors related to onset include obesity,
Stress and lack of exercise are known.

[0003] In diabetes, the impairment of insulin action causes the production of energy due to the insufficient action of insulin.
In order to compensate for this, the breakdown of triglyceride in fat cells is promoted, and fatty acids (FFA) as an energy source
Release is promoted. Decomposition of neutral fat is promoted by activation of hormone-sensitive lipase, but catecholamine, glucagon, adrenal stimulating hormone, etc. activate this enzyme, and conversely, insulin is suppressed. In diabetes, in addition to insulin deficiency, increased secretion of glucagon occurs, which promotes the release of FFA from adipose tissue.

[0004] In addition, at present, there is no other treatment method for type I diabetes than relying on subcutaneous injection of insulin, and there is a demand for the development of a therapeutic drug that can be orally administered instead of insulin. As one of such therapeutic agents, vanadyl sulfate has already been used in clinical trials in the United States and other countries. On the other hand, zinc (II) ion, which is known to be less toxic than vanadium, has been known to have an insulin-like activity since about 1980 (L. Coulston and P. Dandona,
“Insulin-like effect of Zinc on adipocytes”, Diab
etes, 29 , 665-7 (1980); JMMay and CSContoregg
i, “The mechanism of the insulin-like effects of
ionic zinc ", J. Biol. Chem., 257 , 4362-8 (1982); A. Sh
isheva, D. Gefel and Y. Shechter, “Insulin-like eff
ects of zinc ion in vitro and in vivo "(Zn ²⁺ ist
he first agent other than vanadate that on oral ad
ministration is able to restore tissue ability to
metabolism glucose), Diabetes, 41 , 982-8 (1992)).
Since vanadyl sulfate and zinc (II) ion (zinc sulfate and zinc chloride) are inorganic salts, they are difficult to pass through a biological membrane and are hardly taken into a living body. In order to overcome such a problem, it is desired to develop a hypoglycemic agent that is less toxic than vanadium, has better stability, and has a better fat-soluble insulin-like action, and is more effective than the vanadyl complex. I have.

[0005]

SUMMARY OF THE INVENTION The present invention provides a hypoglycemic agent having a lower toxicity than vanadium, a moderate stability, and a moderate lipid-soluble insulin-like action. The present invention also provides an orally administrable hypoglycemic agent having an insulin-like action. As a result of various studies on zinc (II) compounds, the present inventors have found that zinc (II) organic complexes, particularly compounds having a pyridine ring, a pyrone ring, a thiazolidine ring or a thiophene ring, amino acids, 2-aminothiophenol (II) organic complexes having a ligand of thiols or dithiocarbamic acids are less toxic than vanadium, have good stability, and have good fat-soluble insulin-like action,
Furthermore, they have found that these organic complexes of zinc (II) can be administered orally, and have completed the present invention.

[0006]

The present invention relates to a hypoglycemic agent comprising a zinc (II) organic complex, which has a hypoglycemic action and an insulin-like action and is useful as an agent for preventing and treating diabetes. More specifically, the present invention relates to a ligand having a pyridine ring, a ligand having a pyrone ring, a ligand having a thiazolidine ring, a ligand having a thiophene ring, a ligand comprising amino acids, The present invention relates to a hypoglycemic agent comprising a zinc (II) organic complex containing, as a ligand, a ligand composed of aminothiophenols or a ligand composed of dithiocarbamic acids. The present invention also relates to an oral administration preparation comprising a zinc (II) organic complex. Further, the present invention relates to an oral administration preparation comprising a hypoglycemic agent which has a hypoglycemic action and an insulin-like action and is useful as an agent for preventing and treating diabetes.

Further, the present invention relates to a pharmaceutical composition comprising a zinc (II) organic complex and a pharmaceutically acceptable carrier. The present invention also relates to the use of an organic zinc (II) complex for producing a hypoglycemic agent useful as a prophylactic / therapeutic agent for diabetes. The present invention relates to a method for preventing and treating diseases having a high blood sugar level such as diabetes, which comprises administering to a patient a zinc (II) organic complex in a therapeutically effective amount.

Conventionally, it has been known that an inorganic zinc (II) ion compound has an insulin-like action, but the action is not sufficient, and furthermore, it is difficult to pass through a biological membrane and is hardly taken into a living body. , In vivo
It was difficult to expect the effect in o). The present inventors have studied zinc (II) which has good permeability through biological membranes and is easily taken into the living body. As a result, organic complexes of zinc (II) have a large organic portion and It has been found that it has zinc (II) as a metal, has a structure that is easily permeated through a biological membrane and is easily taken into a living body, and has a sufficient insulin-like action and hypoglycemic action.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION As the zinc (II) organic complex of the present invention, Zn (N ₂ O ₂ ) type, Zn (O ₄ ) type, Zn (O
₂ S ₂₎ type, Zn _{(N 2 S} 2) type, or Zn _{(S 4)} type of zinc (II) complexes are preferred. In addition, the zinc of the present invention (I
I) The ligand of the organic complex includes a ligand having a pyridine ring, a ligand having a pyrone ring, a ligand having a thiazolidine ring, a ligand having a thiophene ring, and a ligand comprising amino acids. And a ligand composed of 2-aminothiophenols or a ligand composed of dithiocarbamic acids. As the ligand having a pyridine ring, pyridinecarboxylic acids, pyridylacetic acids, nicotinamide,
Ligands having a pyridine ring and a carboxyl group or a derivative thereof, such as picolinic acid amide, and ligands composed of 2-substituted-pyridine-N-oxide or a derivative thereof are preferable. The ligand having a pyrone ring is preferably a 4-pyrone derivative, more preferably 2-methyl-3-
And a ligand composed of a substituted-4-pyrone derivative. As a ligand having a thiazolidine ring, a ligand having a thiazolidine ring and a carboxyl group or a derivative thereof, such as thiazolidinecarboxylic acids, thiazolidineacetic acids, and thiazolidinecarboxylic acid amides, is preferable.
As the ligand having a thiophene ring, a ligand having a thiophene ring and a carboxyl group or a derivative thereof such as thiophene carboxylic acids, thiophene acetic acids, and thiophene carboxylic acid amides is preferable. Examples of the ligand composed of amino acids include those composed of a compound having an amino group and a carboxyl group, and preferably α-aminocarboxylic acid or a derivative thereof. Preferable examples of the ligand composed of 2-aminothiophenols include ligands composed of 2-aminothiophenol and derivatives thereof having a substituent on a side chain. The ligands composed of dithiocarbamic acids include N, N-
Preferred examples include dialkyl-substituted dithiocarbamic acids, N, N-diaryl-substituted dithiocarbamic acids, and ligands composed of pyrrolidinedithiocarbamic acid and derivatives thereof having a substituent on the side chain. Preferred zinc (II) organic complexes of the present invention include the above-mentioned ligands having a pyridine ring, ligands having a pyrone ring, ligands comprising amino acids, ligands having a thiazolidine ring, and thiophene rings. Zn (N ₂ O ₂ ) having a ligand such as a ligand comprising a 2-aminothiophenol or a ligand comprising a dithiocarbamic acid
Type, Zn (O ₄ ) type, Zn (O ₂ S ₂ ) type, Zn (N ₂
An S ( ₂ ) type or Zn (S ₄ ) type zinc (II) organic complex may be used.

The preferred zinc (II) organic complex ligands of the present invention are described in more detail below. Zinc (II) of the present invention
Preferred examples of the ligand having a pyridine ring of the organic complex include the following general formula (1):

[0011]

Embedded image

(Wherein R ₁ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group,
An alkoxy group, an amino group which may be substituted, or a heterocyclic group which may have a substituent, wherein each R ₁ may be independently two or more on a pyridine ring, and X ₁ is , A lower alkoxy group, an amino group which may be substituted with a lower alkyl group, or a hydroxyl group, and n represents an integer of 0-5. A) a carboxylic acid derivative having a pyridine ring. The substituent R in the general formula (1)
₁ is not particularly limited to those described above as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention, and may be bonded to any position of the pyridine ring. And two or more substituents, for example, R ₁ groups may be bonded on the pyridine ring. Group-C
OX ₁ represents a carboxyl group or a derivative thereof, and is not limited thereto as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention. Further, the group — (CH ₂ ) _n —COX ₁ may be bonded to any position of the pyridine ring. N is 0
It represents an integer of ~ 5, but is not particularly limited to this value as long as it can coordinate with zinc of the central metal and does not inhibit the insulin-like action or hypoglycemic action of the present invention. , Preferably 0-5, more preferably 0
3, and more preferably an integer of 0 to 1.

Other preferred examples of the ligand having a pyridine ring of the zinc (II) organic complex of the present invention include the following general formula (2):

[0014]

Embedded image

(Wherein R ₂ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group,
Represents an alkoxy group, an amino group which may be substituted, or a heterocyclic group which may have a substituent, wherein each R ₂ may be independently two or more on a pyridine ring, and R ₃ is , A mercapto group, an amino group which may be substituted, or a hydroxyl group. ) Is a derivative of pyridine-N-oxide. The substituent R ₂ in the general formula (2) is not particularly limited to the above-mentioned ones as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention. It may be bonded to any of the 4-, 5-, or 6-positions, and two or more substituents, for example, R ₂ groups may be bonded on the pyridine ring. The group R ₃ is a mercapto group as long as it can bond to the central metal zinc by a coordination bond or a covalent bond.
It is not limited to an amino group or a hydroxyl group which may be substituted, but is preferably a mercapto group, an amino group or a hydroxyl group, more preferably a mercapto group or a hydroxyl group.

Preferred examples of the ligand having a pyrone ring of the zinc (II) organic complex of the present invention include 4-pyrone derivatives, more preferably 2-substituted or unsubstituted methyl-3-substituted. -4-pyrone or a derivative thereof. Preferred derivatives of 4-pyrone include the following general formula (3):

[0017]

Embedded image

(Wherein R ₄ and R ₅ each independently represent a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted Represents a heterocyclic group which may have a substituent,
Each of R ₄ may be independently two on the pyrone ring, and R ₆ represents a hydrogen atom, a mercapto group, an amino group which may be substituted, or a hydroxyl group. )). The substituent R ₄ in the general formula (3) is not particularly limited as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention. Place or 6
At any of the positions, and each independently has two substituents at both the 5- and 6-positions, such as R
_Four groups may be bonded on the pyrone ring. The group R ₅ is 2
The substituent is not particularly limited to those described above as long as it is a substituent of the methyl group at the position and does not inhibit the insulin-like action or hypoglycemic action of the present invention.
The methyl group at the position may be substituted with two or three substituents. The group R ₆ is not limited to a hydrogen atom, a mercapto group, an amino group which may be substituted, or a hydroxyl group, as long as the group R ₆ can bind to zinc of the central metal by a coordination bond or a covalent bond. It is preferably a hydrogen atom, a mercapto group, an amino group, or a hydroxyl group, and more preferably a hydroxyl group.

Examples of the ligand comprising an amino acid of the zinc (II) organic complex of the present invention include an α-amino acid or a derivative thereof. More preferable examples include the following general formula (4):

[0020]

Embedded image

(Where R₇Is a hydrogen atom, a hydroxyl group
Is an aralkyl optionally substituted with a lower alkoxy group
Group, substituted or unsubstituted heterocyclic group, hydroxyl group, lower alkyl group
Coxy group, guanidino group, amino group, carboxyl group,
Carbamoyl group, thiol group or lower alkylthio
A lower alkyl group which may be substituted with
Or R₇And R₈Together represent a lower alkylene group
You. R₈Are the same or different and represent a hydrogen atom, a lower alkyl
And a lower alkylcarbonyl group. X ₂Is
Even if it is substituted with a lower alkoxy group or a lower alkyl group
Shows a good amino group or hydroxyl group. Amino represented by)
Acids or derivatives thereof. Group R₇Is α-amino
A substituent on the alpha carbon atom of the acid,
If it does not inhibit the action or hypoglycemic action,
It is not particularly limited to the above. Group-C
OX₂Represents a carboxyl group or a derivative thereof.
And inhibits the insulin-like action or hypoglycemic action of the present invention.
It is limited to these if it does not harm
Nor. Also, R₈Is a substituent of an amino group,
Are preferred, but not limited to,
Acyl groups such as alkyl groups and lower alkylcarbonyl groups
And various amino acids used in peptide chemistry, etc.
It may be a substituted amino group substituted with a protecting group or the like
And a salt-forming amino group or a combination thereof.
It may be. R mentioned above₇And R₈Together
When it represents a lower alkylene group, it is adjacent to these groups.
A ring consisting of carbon and nitrogen atoms is formed. example
For example, when the lower alkylene group is a propylene group,
-Membered ring containing nitrogen atom together with carbon and nitrogen atoms
Is formed, and as a whole is a kind of natural α-amino acid
It becomes a certain proline. Thus, the α-amino of the present invention
Acids also include amino acids containing rings such as proline
are doing.

As the ligand comprising the 2-aminothiophenol of the zinc (II) organic complex of the present invention, 2-aminothiophenol or a derivative thereof is mentioned, and a more preferable example is the following general formula: (5),

[0023]

Embedded image

(Wherein R ₉ is a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group,
It represents an alkoxy group, an amino group which may be substituted, or a heterocyclic group which may have a substituent, and two or more R ₉ may be independently present on the benzene ring. ) Or a derivative thereof. The substituent R ₉ in the general formula (5) is not particularly limited to those described above as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention. May be bonded, or two or more substituents, for example, R ₉ group may be bonded on the benzene ring.

As the ligand comprising the dithiocarbamic acid of the zinc (II) organic complex of the present invention, dithiocarbamic acid or a derivative thereof is mentioned. More preferable examples are the following general formula (6):

[0026]

Embedded image

(Wherein, R ₁₀ and R ₁₁ each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent. In addition, R ₁₀ and R ₁₁ together form a substituent. May form an alkylene group which may be possessed) or a derivative thereof. Particularly preferred examples of the dithiocarbamic acid or a derivative thereof represented by the above general formula (6) include the following general formula (7):

[0028]

Embedded image

(Wherein R ₁₂ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, A heterocyclic group which may be present, and two or more of R ₁₂ may be independently present on the pyrrolidine ring.)
And pyrrolidinedithiocarbamic acid or a derivative thereof. The substituent R in the general formula (7)
₁₂ is not particularly limited as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention, and may be bonded to any position of the pyrrolidine ring. , Further two or more substituents,
For example, the R ₁₂ group may be attached on the pyrrolidine ring.

Preferred examples of the ligand having a thiazolidine ring of the zinc (II) organic complex of the present invention include the following general formula (8):

[0031]

Embedded image

(Wherein R ₁₃ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, indicates also heterocyclic group, the R ₁₃ may be independently present two on the thiazolidine ring, X ₃
Represents a lower alkoxy group, an amino group which may be substituted with a lower alkyl group, or a hydroxyl group, and m represents an integer of 0 to 5. And a carboxylic acid derivative having a thiazolidine ring. The substituent R ₁₃ in the general formula (8) is not particularly limited to the above-mentioned one as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention.
Or any of the 2-, 4-, and 5-positions.
Two substituents, for example, R ₁₃ group may be bonded on the thiazolidine ring at each position. The group -COX ₃ represents a carboxyl group or a derivative thereof, and is not limited thereto as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention. In addition, the group
(CH ₂ ) _m -COX ₃ may be bonded to any of the 2-, 4- and 5-positions of the thiazolitin ring. Also,
m represents an integer of 0 to 5, but can be coordinated with zinc as a central metal, and is particularly limited to this value unless the insulin-like action or hypoglycemic action of the present invention is inhibited. However, it is preferably an integer of 0 to 5, more preferably 0 to 3, and still more preferably 0 to 1.

Preferred examples of the ligand having a thiophene ring of the zinc (II) organic complex of the present invention include the following general formula (9):

[0034]

Embedded image

(Wherein R ₁₄ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, And R ₁₄ may be independently two or more on the thiophene ring;
₄ represents an amino group which may be substituted with a lower alkoxy group, a lower alkyl group, or a hydroxyl group, and k represents an integer of 0 to 5. And a carboxylic acid derivative having a thiophene ring. The substituent R ₁₄ in the general formula (9) is not particularly limited as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention. May be bonded, or two or more substituents, for example, R ₁₄ groups may be bonded on the thiophene ring. The group -COX ₄ represents a carboxyl group or a derivative thereof, and is not limited thereto as long as it does not inhibit the insulin-like action or hypoglycemic action of the present invention. Further, the group — (CH ₂ ) _k —CO
X ₄ may be bonded to any position of the thiophene ring. Further, k represents an integer of 0 to 5, but is particularly limited to this value as long as it can coordinate with zinc of the central metal and does not inhibit the insulin-like action or hypoglycemic action of the present invention. However, it is preferably an integer of 0 to 5, more preferably 0 to 3, and even more preferably 0 to 1.

Substituent R for pyridine, pyrone, benzene, pyrrolidine, thiazolidine and thiophene rings
₁ , R ₂ , R ₄ , R ₉ , R ₁₂ , R ₁₃ , R _{14 and} the substituent R ₅ of the methyl group at the 2-position of the pyrone ring do not inhibit the insulin-like action or hypoglycemic action of the present invention. , Various organic residues can be used, but a hydrocarbon group which may have a substituent, a halogen atom,
Preferred are a hydroxyl group, an alkoxy group, an amino group which may be substituted, a heterocyclic group which may have a substituent, and the like.

The hydrocarbon group includes a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group and the like. The “lower alkyl group” in the present invention has 1 to 15, preferably 1 to 10, more preferably 1 to 1 carbon atoms.
To 6, more preferably 1 to 4 linear or branched alkyl groups, and more specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, Secondary butyl group, tertiary butyl group,
Examples include a pentyl group and a hexyl group.
Examples of the “lower alkenyl group” include a linear or branched alkenyl group having 2 to 15, preferably 2 to 10, and more preferably 2 to 6 carbon atoms. More specifically, for example, a vinyl group , Allyl group, butenyl group, pentenyl group and the like. Examples of the “lower alkynyl group” include a linear or branched alkynyl group having 2 to 15, preferably 2 to 10, and more preferably 2 to 6 carbon atoms, and more specifically, for example, an ethynyl group , Propynyl group, butynyl group, pentynyl group and the like.

The "cycloalkyl group" includes 3 to 30 carbon atoms, preferably 5 to 20 carbon atoms, and more preferably 6 carbon atoms.
And a monocyclic, polycyclic or condensed cyclic alkyl group of from 10 to 10. As the "cycloalkenyl group", those having an unsaturated group such as one or more double bonds in the above cycloalkyl group are mentioned. No. As the "aryl group",
A monocyclic, polycyclic or condensed-ring aromatic hydrocarbon group having 6 to 30, preferably 6 to 20, and more preferably 6 to 10 carbon atoms is exemplified. The "lower alkylene group" has 1 to 15, preferably 1 to 10, more preferably 1 to 1 carbon atoms.
6, more preferably 1 to 4 linear or branched alkylene groups. When these lower alkylene groups form a ring together with adjacent atoms, one or more carbon atoms in the lower alkylene group may be substituted with an oxygen atom, a nitrogen atom or a sulfur atom.

The above "hydrocarbon group" may further have a substituent. Examples of these substituents include a lower alkoxy group derived from the aforementioned lower alkyl group, a hydroxyl group, an amino group, a halogen atom, a heterocyclic group, a nitro group, and the like. The “halogen atom” includes chlorine, bromine, iodine and the like. As the “alkoxy group”, a lower alkoxy group derived from the lower alkyl group described above is preferable. Examples of the substituent of the “optionally substituted amino group” include the aforementioned hydrocarbon groups and acyl groups derived from these hydrocarbon groups.

The term "heterocyclic group" means that the ring has at least one nitrogen, oxygen or sulfur atom,
Each ring has 5 to 20 members, preferably 5 to 10 members, more preferably 5 to 7 members, and may be condensed with a carbocyclic group such as a cycloalkyl group, a cycloalkenyl group or an aryl group. Examples include well-saturated or unsaturated monocyclic, polycyclic or condensed cyclic ones. The above-mentioned heterocyclic group may further have a substituent, and as these substituents, a lower alkoxy group derived from the above-mentioned lower alkyl group,
Examples include a hydroxyl group, an amino group, a halogen atom, a heterocyclic group, and a nitro group.

The zinc (II) organic complex of the present invention can be produced by a known method (for example, US Pat. No. 5,219,847) or according to these known methods. For example, it can be produced by adding a zinc salt solution to a solution of a target ligand to form a zinc (II) organic complex, and isolating this. Usually, water is preferred as the solvent, but an organic solvent or a mixed solvent can also be used. As the zinc salt solution, an aqueous solution of an inorganic zinc such as zinc sulfate, zinc nitrate, and zinc chloride is preferable.
The pH of the reaction solution is preferably adjusted as necessary. p
As a regulator of H, a basic aqueous solution such as sodium hydroxide, lithium hydroxide and barium hydroxide can be used. More specifically, reference can be made to the embodiments described below.

The zinc (II) organic complex of the present invention has an insulin-like action or a hypoglycemic action, as is clear from the test examples described later, and is useful as an agent for preventing or treating diabetes or hypertension. Therefore, the present invention provides a pharmaceutical composition comprising the above-mentioned zinc (II) organic complex of the present invention and a pharmaceutically acceptable carrier.

For the formulation, the zinc (II) organic complex of the present invention is used as an active ingredient and a pharmaceutical such as an organic or inorganic solid or liquid excipient suitable for oral administration, parenteral administration or topical administration. Can be used in the form of a pharmaceutical preparation containing the carrier as an acceptable carrier. The pharmaceutical preparations may be capsules, tablets, sugars, granules, inhalants, suppositories, solutions, lotions, suspensions, emulsions, ointments, gels and the like. If necessary, the above preparations may contain adjuvants, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives. The present invention also provides an oral administration preparation containing an organic zinc (II) complex.
The oral administration preparation of the present invention is an oral administration preparation containing a zinc (II) organic complex having an insulin-like action or a hypoglycemic action. Therefore, the present invention provides a preventive / therapeutic preparation for diabetes which can be orally administered. Also,
Use of an organic zinc (II) complex for producing an orally administrable prophylactic / therapeutic preparation for diabetes, and a method for preventing / treating diabetic comprising orally administering an effective amount of an orally administrable prophylactic / therapeutic preparation for diabetes Is provided.

The effective dose of the organic zinc (II) complex of the present invention in the prevention and / or treatment varies depending on the age and symptoms of the patient, but the average single dose of the organic zinc (II) complex of the present invention is about 0.1. A dose of 1 mg / person to about 1000 mg / person may be administered once or several times a day.

Next, using the zinc (II) organic complex of the present invention,
Effects of fatty acid release on isolated rat adipocytes
1 and 2 show the results of the tests. 1 and 2
Indicates that all of these were found in rat adipocytes stimulated with epinephrine.
Of free fatty acids when the zinc (II) organic complex of the invention is added
This shows the suppression effect. 1 in FIG. 1 is blank,
2 is control, 3-5 are oxovanadium sulfate (V
OSO₄), 6-26
Indicates a sample using the compound of the present invention. 6-8 are zinc
(II) Picolinic acid complex [Zn (PA)₂(H
₂O)₂9-11 are zinc (II) 6-methyl-picoli
Acid complex [Zn (MPA)₂(H₂O)], 12-14
Is a zinc (II) pyridine-2-acetic acid complex [Zn (PAA)
₂(H₂O) ₂] 15 to 17 are zinc (II) glycine complexes
Body [Zn (Gly)₂(H₂O)], 18-20 are zinc
(II) threonine complex [Zn (Thr)₂(H
₂O)₂And 21 to 23 are zinc (II) maltol complexes.
2.6 hydrate, Zn (maltol)₂/2.6H
₂O, 24-26 are zinc (II) 2-mercaptopyridine
Oxide complex [(Zn (MPNO)₂)₂].
The concentration of the compound used was 10 for each of 3 to 23.^-4M,
5 × 10^-4M, 10 ^-3M, 24 to 26 are each 5 × 1
0^-5M, 2.5 × 10^-4M, 5 × 10^-4M
Was.

In FIG. 2, 1 is blank and 2 is control.
Rolls 3-5 are oxovanadium sulfate (VOSO)₄)
Positive control using 6 to 14 of the present invention
An example using a compound is shown. 6 to 8 are zinc (II) 2-a
Minothiophenol complex [Zn (ABT)₂], 9-1
1 is a zinc (II) pyrrolidine-N-dithiocarbamate complex
Body [Zn (PCD) ₂], 12 to 14 are zinc (II) cis
Thein methyl ester complex [Zn (Cys-OM
e)₂]. The concentrations of the compounds used were 3-5 and
12-14 are 10 each^-4M, 5 × 10 ^-4M, 10
^-3M, 6-8 and 9-11 are each 10^-5M, 5 × 1
0^-5M, 10^-4M.

In FIG. 1 and FIG. 2, 1 “blank” indicates the value of free fatty acid (FFA) due to spontaneous release of cells, and 2 “control” indicates the value of epinephrine released by stimulation. Also, 3 to 5 in FIGS.
"VOSO ₄ " in the above indicates oxovanadium sulfate as a comparative example. In addition, various zinc (II) compounds of the present invention were calculated based on these test results and the test results of the zinc (II) complex of the present invention other than the above obtained in the same manner.
The following Table 1 shows the IC ₅₀ (mM) value of the complex, which indicates the concentration of the test drug that inhibits the release of fatty acids by 50%. Table 1 shows that the IC ₅₀ (mM) of “VOSO ₄ ” is 1.00 m
M is shown as a relative value. In addition, 6-methyl-
Picolinic acid complex [Zn (MPA) ₂ (H ₂ O)] and zinc (II) pyridine-2-acetic acid complex [Zn (PAA)
₂ (H ₂ O) ₂ ] in DMSO (dimethylsulfoxide) in a zinc (II) glycine complex [Zn (Gly) ₂
(H ₂ O)] is the result of measurement in an aqueous solution and the others in a physiological saline solution.

[0048]

[Table 1]

[0049] As shown from these results, the zinc (II) of the present invention complexes can be significantly suppressed the release of fatty acids from rat adipose cells compared to VOSO _4,
It has been revealed that it is excellent as a drug for preventing and treating diabetes and a drug for preventing and treating hypertension.

Next, the type 2 diabetes model animal KK-
A^yFig. 3 shows the blood glucose curves during the glucose tolerance test in mice and humans.
4 and FIG. (A) in FIG. 3 shows the zinc (II) of the present invention.
Complex Zn (PA)₂(H₂O) ₂Once a day, 4
mg / kg for 3 days and then fasted for 14 hours.
Fig. 4 shows a blood glucose curve at the time of a glucose tolerance test for a mouse, and (b)
Indicates that of the control, uncomplexed mice.
This is shown. In addition, (a) in FIG.
The blood glucose curve at the time of the load test is shown, and (b) shows that of a healthy person.
Show.

FIG. 4 shows the results of a glucose tolerance test used for the examination of diabetes in humans [Ayako Hakura, “Japanese Diabetes 3 (Special Issue), Diabetes 3”, No. 728, p. 419).
(Nippon Clinical Co., Ltd.)], as is clear from this figure, in a healthy person with normal glucose metabolism, a slight increase in blood glucose level was observed after oral administration of glucose, but the blood glucose level rapidly decreased to 180 minutes. Later, it recovers to the blood glucose level before administration. On the other hand, in a diabetic patient having abnormal glucose metabolism, the blood glucose level rises to about twice that of a healthy person, hyperglycemia continues for a while, and does not recover to the blood glucose level before administration of glucose even after 180 minutes. In contrast, in the glucose tolerance test of KK- ^Ay mice, as is clear from FIG. 3, the zinc (II) complex of the present invention, Zn
After administering (PA) ₂ (H ₂ O) ₂ once a day at 4 mg / kg for 3 days, the mice that were fasted for 14 hours showed more glucose administration than the mice that did not receive the complex. The blood glucose level had a low peak top, and the blood glucose level rapidly decreased, and after 180 minutes, the blood glucose level was almost restored to a normal value. The above results show that mice administered with the zinc (II) complex of the present invention have improved type 2 diabetes.

[0052]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 (Bis (picolinate) zinc (I
I) Complex, [Zn (PA)₂(H₂O) ₂The method of Lume et al. (P. Lumme, et al., Acta Chemica Scandi)
navica,twenty three, 3011-22 (1969))
Picolinic acid (10m
M) was dissolved. Add zinc (II) sulfate (5 mM) to the solution.
The aqueous solution was added dropwise little by little with stirring. A few days later,
The precipitate formed is filtered off, washed thoroughly with water and dried to give a white target substance.
3.26 g (yield 90%) was obtained. The obtained transformer
Bis (picolinate) zinc (II) complex [Zn (PA)₂
(H₂O)₂] Is shown in the following formula.

[0054]

Embedded image

Example 2 A zinc (II) 6-methyl-picolinic acid complex [Zn (MPA) ₂ (H ₂ O)] was produced according to the method of Example 1.
The structure of the obtained bis (6-methyl-picolyl Nate) zinc (II) complex _{[Zn (MPA) 2 (H} 2 O)] are shown in the following equation.

[0056]

Embedded image

Example 3 The method of Faure et al. (PRFaure, et al., Acta Cryst.,
B28 , 811-5 (1972)), bis (pyridine-2-acetate) zinc (II) complex [Zn (PAA) ₂ (H ₂ O)
₂ ] was produced. The resulting trans-bis (pyridine-
2-acetate) zinc (II) complex [Zn (PAA)
₂ (H ₂ O) ₂ ] is shown in the following formula.

[0058]

Embedded image

Example 4 Method of Hamalainen (R. Hamalainen, Finn. Chem. Lett.,
1977 , 113), bis (threonine) zinc (II)
The complex [Zn (Thr) ₂ (H ₂ O) ₂ ] was produced. The obtained cis-bis (threonine) zinc (II) complex [Zn
(Thr) ₂ (H ₂ O) ₂ ] is shown in the following formula.

[0060]

Embedded image

Example 5 The method of Newman et al. (J. M. Newman, et al., Acta Crys)
t.,C46, 44-8 (1990)).
Lead (II) complex [Zn (Gly)₂(H₂O)]
Was. Trans-bis (glycine) zinc (II) complex obtained
Body [Zn (Gly)₂(H ₂O)]
It is shown in the following equation.

[0062]

Embedded image

Example 6 Bis (3-hydroxy-2-methyl-4-pyronate)
Zinc (II) complex [Zn _{(maltol) 2} /2.6H 2
O] Production of maltol (3-hydroxy-2-methyl-4-pyrone) (10
mM). An aqueous solution of zinc (II) sulfate · 7 hydrate (5 mM) was added dropwise to the solution with stirring. The resulting precipitate was separated by filtration, sufficiently washed with water, and dried to obtain 0.588 g (yield: 32.5%) of a white target product. Molecular formula:
Zn (C ₆ H ₅ O ₃ ) ₂ /2.6H ₂ O, molecular weight: 361.8 elemental analysis Calculated value (%) C: 39.77, H: 4.23, N: 0.00. Obtained value (%) C: 39.66, H: 4.14, N: 0.02. IR: Full chart is shown in FIG.

Example 7 Preparation of bis (2-mercaptopyridine-N-oxide) zinc (II) complex [(Zn (MPNO) ₂ ) ₂ ] 2-mercaptopyridine-N- complex was added to 10 ml of an aqueous solution of sodium hydroxide (10 mM). Oxide (10 mM) was dissolved. After 30 minutes, the pH was adjusted to 8 with 1 M HCl.
Further, after 30 minutes, zinc (II) sulfate · 7-hydrate (5 mM)
The aqueous solution was added in small portions with stirring. The resulting precipitate was separated by filtration, sufficiently washed with water, and dried to obtain 0.714 g of a white target substance.
(44.2% yield). The structure of the obtained dinuclear bis (2-mercaptopyridine-N-oxide) zinc (II) complex is shown by the following formula (BLBarnett., Et al., Inorg.Che.
m., 16, 1834-1838 (1977)).

[0065]

Embedded image

Example 8 Bis (2-aminothiophenol) zinc (II) complex [Z
_{n (ABT) 2 /0.5H 2 O} ] Using 2-amino-benzenethiol (ABT) 250mg (2
85 mg (2 mM) in methanol solution of lithium hydroxide.
An aqueous solution of zinc (II) sulfate heptahydrate 288 mg (1 mM) was added to the solution after several hours. After stirring overnight, the insolubles were collected by filtration, washed several times with pure water, and dried under reduced pressure to obtain the desired product in a yield of 78%.

Example 9 Bis (pyrrolidine-N-dithiocarbamate) zinc (I
I) complex _{[Zn (PCD) 2 /0.2H 2} O] Production ammonium pyrrolidine -N- carbonitrile dithio Eight (A
492 mg (3 mM) of PCD) was dissolved in 5 ml of 0.8 M aqueous sodium hydroxide solution, and the solution was adjusted to pH 8 with 1 M hydrochloric acid. Further, when an aqueous solution of 431 mg (1.5 mM) of zinc (II) sulfate heptahydrate was added to the solution, the pH became almost 6. After several hours, the resulting white insoluble matter (precipitate) was collected by filtration, washed several times with pure water, and dried under reduced pressure to obtain the desired product in a yield of 96%.

Example 10 Preparation of bis (L-cysteine methyl ester) zinc (II) complex [Zn (Cys-OMe) ₂ ] L-cysteine methyl ester hydrochloride [(Cys-OM)
e) .HCl] To an aqueous solution of 514 mg (3 mM) was added an aqueous solution of 945 mg (3 mM) of barium hydroxide octahydrate, and after several hours, the zinc (II) sulfate heptahydrate 43 was added.
An aqueous solution of 1 mg (1.5 mM) was added. After stirring overnight, the insoluble matter (precipitate) was collected by filtration, and the amount of the filtrate was reduced to about one half.
After concentration, the resulting precipitate was collected by filtration, washed several times with methanol, and dried under reduced pressure to obtain the desired product in a yield of 42%.

Pharmacological Test Example 1 The pharmacological test was performed in the following manner according to the method described in Biol. Pharm. Bull., 18 , 719-725 (1995).

Isolation of Rat Adipocytes Male Wistar rats weighing 200 g were killed by exsanguination under ether anesthesia, and were subjected to a rod-bell method (J. Biol. Chem.,
239 , 375 (1964)), adipocytes were separated from adipose tissue around epididymis. The adipocytes were cut with scissors and KRB buffer (5 mM glucose, 120 mM NaCl, 1.27 mM CaC) containing 20 mg bovine serum albumin (BSA) and 2 mg collagenase per ml.
₁₂ , 1.2 mM MgSO ₄ , 4.75 mM KC
1, 1.2 mM KH ₂ PO ₄ , and 24 mM NaH
Digestion was carried out at 37 ° C. for 1 hour in CO ₃ ; pH = 7.4).
Adipocytes were separated from undigested tissue by filtration through a nylon mesh (250 μm), washed three times with the above buffer without collagenase, and
^It was adjusted to ⁶ cells / ml.

The zinc (II) complex on rat adipocytes
Effect The oil separated above in a siliconized vial
Fat cells (2.5 × 10 ⁶Cells / ml) at various concentrations (1
0^-4, 5 × 10^-4, 10^-3) VOSO ₄And book
20 mg BSA / ml of various Zn (II) organic complexes of the invention
In 1 mL of KRB buffer at 37 ° C for 0.5 hour
Pre-incubated for a while. Then 10^-5Episode M
Nephrin was added to the reaction mixture and the resulting solution was
Incubated for 3 hours. The reaction was stopped by ice cooling,
The mixture was centrifuged at 3000 rpm for 10 minutes. cell
For external solutions, the free fatty acid (FFA) level
A using IC kit₅₀Was calculated. The result
1 and 2 and Table 1. As a result, the zinc of the present invention
(II) The organic complex is VOSO₄Rat fat fine compared to
Can significantly suppress the release of fatty acids from the vesicles,
It was found to be excellent as a therapeutic agent for urine.

Pharmacological Test Example 2 <Experimental Method> Eight-week-old KK- ^Ay mice were used, a 5% acacia solution (n = 6) as a control group, and Zn (PA) ₂ (n = 6) as a complex administration group. ), Zn (malto
l) ₂ (n = 7) and Zn (Cys-OMe) ₂ (n =
6) was dissolved in a 5% acacia solution and administered intraperitoneally once a day. The dose was 4.5 mg Zn / Kg for mice whose blood glucose level was 200 mg / dL or more, and 150 mg / dL or more
Mice below 00 mg / dL were given 2.5 mg Zn / Kg, whereas mice below 150 mg / dL were not administered. In addition, as a control, an acacia solution was added to 0.1 ml.
Each 5 ml was administered. The presence or absence of diabetes was confirmed by an average blood glucose level immediately before administration of 450 mg / dL or more and an average body weight of 35 g or more. The measurement of the blood sugar level was performed using a simple blood sugar level measuring device (Gluco Card: manufactured by Kyoto Daiichi Kagaku Co., Ltd.).

<Results and Discussion> FIG. 6 shows changes in blood glucose level as a result of administering Zn (PA) ₂ for 15 days. Zn (malto
l) Changes in blood glucose level as a result of administration of ₂ for 15 days are shown in FIG. FIG. 8 shows the change in blood glucose level as a result of administering Zn (Cys-OMe) ₂ for 13 days. FIG. 9 shows the change in body weight as a result of administering Zn (PA) ₂ for 15 days. Zn (maltol)
FIG. 10 shows the change in body weight as a result of administering No. ₂ for 15 days.
FIG. 11 shows the change in body weight as a result of administering Zn (Cys-OMe) ₂ for 13 days. The results of a glucose tolerance test performed after administration of the complex for 15 days are shown in FIG. (Sugar tolerance test:
A test method in which 1 g / kg of glucose is orally administered to mice after a 13-hour fast, and blood glucose levels are measured at regular intervals after administration. 6 to 12, (a) is a control, (b) is a group to which a complex Zn (PA) ₂ is administered, and (c) is a complex Zn (malt).
ol) ₂ , and (d) shows the complex Zn (Cys-OM).
e) The results for the groups to which ₂ was administered are shown.

In the group to which the complex was administered, a higher blood glucose level normalizing effect was observed in all three types of complexes than in the control group (FIGS. 6 to 8). Weight loss, which is one of the indicators of side effects, was hardly observed in the group to which Zn (PA) ₂ was administered (FIG. 9). In the group to which Zn (maltol) ₂ was administered, a decrease in body weight was observed immediately after the administration of the complex, but the blood glucose level began to decrease and the body weight recovered as the dose decreased (FIG. 10). In the group to which Zn (Cys-OMe) ₂ was administered, no increase or decrease in body weight was observed (FIG. 11). This phenomenon suppresses the weight gain of obese KK- ^Ay mice, which is a type 2 diabetes model animal, and it can be seen that diabetes has been improved. Furthermore, the Zn (PA) ₂ complex and the Zn (maltol) ₂ complex were administered with the complex for 15 days and then subjected to a glucose tolerance test. As a result, the diabetic state was improved as compared with the diabetic mouse (control mouse). (Fig. 12).

[0075]

Industrial Applicability The zinc (II) organic complex of the present invention has a high stability and has a fat-soluble insulin-like action and an antihypertensive action. Therefore, the zinc (II) complex of the present invention has impaired glucose tolerance,
Diabetes (such as type II diabetes), insulin resistance syndrome (such as insulin receptor dysfunction), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disease (such as angina and heart failure), Hyperglycemia, or hypertension, or angina, hypertension, pulmonary hypertension, congestive heart failure,
Diabetic complications (eg diabetic necrosis, diabetic arthropathy,
It is useful as a medicament used as a prophylactic / therapeutic agent for diabetic glomerulosclerosis, diabetic skin disorder, diabetic neuropathy, diabetic cataract, diabetic retinopathy and the like.

[Brief description of the drawings]

FIG. 1 shows the effect of the organic zinc (II) complex of the present invention on fatty acid release from adipocytes.
In FIG. 1, 1 is a blank, 2 is a control, 3 to 5 are positive controls, and 6 to 26 are compounds of the present invention.

FIG. 2 shows the effect of the organic zinc (II) complex of the present invention on fatty acid release from adipocytes.
In FIG. 1, 1 is a blank, 2 is a control, 3 to 5 are positive controls, and 6 to 14 are compounds of the present invention.

FIG. 3 shows blood glucose curves during a glucose tolerance test on KK- ^Ay mice with and without administration of the zinc (II) organic complex of the present invention.

FIG. 4 shows a blood glucose curve during a glucose tolerance test on humans (diabetic patients and healthy subjects).

FIG. 5 shows bis (3-hydroxy-2-) of the present invention.
Methyl-4-pyranate) zinc (II) complex Zn (malto
l) Infrared absorption spectrum (IR) of _{2 /} 2.6H ₂ O
3 is a full chart of FIG.

FIG. 6 shows a zinc (II) organic complex Zn (P) of the present invention.
A) Changes in blood glucose level as a result of administration of ₂ for 15 days.

FIG. 7 shows a zinc (II) organic complex Zn (ma) of the present invention.
(ltol) ₂ shows changes in blood glucose levels as a result of administration for 15 days.

FIG. 8 shows a zinc (II) organic complex Zn (C) of the present invention.
5 shows changes in blood glucose levels as a result of administration of ys-OMe) ₂ for 13 days.

FIG. 9 shows a zinc (II) organic complex Zn (P) of the present invention.
A) Changes in body weight as a result of administration of ₂ for 15 days.

FIG. 10 shows a zinc (II) organic complex Zn of the present invention.
(Maltol) Changes in body weight as a result of administration of ₂ for 15 days.

FIG. 11 shows a zinc (II) organic complex Zn of the present invention.
The change in body weight as a result of administering (Cys-OMe) ₂ for 13 days is shown.

FIG. 12 shows one example of the zinc (II) organic complex of the present invention.
The results of a glucose tolerance test performed after administration for 5 days are shown.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/351 A61K 31/351 4C086 31/381 31/381 4C206 31/40 31/40 31/426 31 / 426 31/44 31/44 31/4402 31/4402 31/555 31/555 A61P 3/10 A61P 3/10 43/00 111 43/00 111 // C07D 207/06 C07D 207/06 213/55 213 / 55 213/79 213/79 213/80 213/80 213/89 213/89 277/06 277/06 309/38 309/38 309/40 309/40 333/40 333/40 333/40 F-term (reference) 4C023 HA02 4C033 AB05 AB20 4C055 AA01 AA17 BA01 BA02 BA03 BA06 BA33 BA39 BA42 BA47 BA57 CA01 CA57 DA01 GA02 4C062 DD12 DD13 4C069 AA02 BD08 4C086 AA01 AA02 BA07 BB02 BC07 BC17 BC19 BC82 MA01 MA04 NA14 ZC02 ZC01 A02 MA72 NA14 ZC02 ZC35

Claims (25)

[Claims] 1. A hypoglycemic agent comprising a zinc (II) organic complex. 2. The hypoglycemic agent according to claim 1, wherein the hypoglycemic agent is a preventive or therapeutic agent for diabetes. 3. The hypoglycemic agent according to claim 1, wherein the zinc (II) organic complex has a ligand having a pyridine ring. 4. The ligand having a pyridine ring of an organic zinc (II) complex is represented by the following general formula (1): (Wherein, R ₁ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, and a hetero group which may have a substituent. A ring group, two or more of the R ₁ may be independently present on the pyridine ring, and X ₁ is a lower alkoxy group, an amino group optionally substituted with a lower alkyl group, or a hydroxyl group. And n represents an integer of 0 to 5).) The hypoglycemic agent according to claim 3, which is a carboxylic acid derivative having a pyridine ring. 5. The hypoglycemic agent according to claim 3, wherein the ligand having a pyridine ring of the zinc (II) organic complex is a pyridine-N-oxide derivative. 6. The ligand having a pyridine ring of a zinc (II) organic complex is represented by the following general formula (2): (Wherein R ₂ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, and a heterocyclic ring which may have a substituent. R ₂ may be independently present on the pyridine ring two or more times, and R ₃ represents a mercapto group, an amino group which may be substituted, or a hydroxyl group.) 6. A derivative of pyridine-N-oxide.
The hypoglycemic agent according to the above. 7. The hypoglycemic agent according to claim 1, wherein the zinc (II) organic complex has a ligand having a pyrone ring. 8. The hypoglycemic agent according to claim 7, wherein the ligand having a pyrone ring is a derivative of 4-pyrone. 9. A derivative of 4-pyrone is represented by the following general formula (3): (Wherein R ₄ and R ₅ each independently represent a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted,
R ₄ represents a heterocyclic group which may have a substituent; R ₄ may be independently two on the pyrone ring; R ₆ is a hydrogen atom, a mercapto group, an amino group which may be substituted; And a hydroxyl group. 9. The hypoglycemic agent according to claim 8, which is a derivative of 4-pyrone represented by the formula: 10. The hypoglycemic agent according to claim 1, wherein the zinc (II) organic complex has an amino acid as a ligand. 11. An amino acid represented by the following general formula (4): (In the formula, R ₇ represents a hydrogen atom, an aralkyl group which may be substituted with a hydroxyl group or a lower alkoxy group, or a substituted or unsubstituted heterocyclic group, a hydroxyl group, a lower alkoxy group, a guadinino group, an amino group, a carboxy group. A lower alkyl group which may be substituted with a carbamoyl group, a thiol group or a lower alkylthio group;
₇ and R ₈ together represent a lower alkylene group. R ₈
Is the same or different and represents a hydrogen atom, a lower alkyl group, or a lower alkylcarbonyl group. X ₂ represents a lower alkoxy group, an amino group which may be substituted with a lower alkyl group, or a hydroxyl group. 11. The hypoglycemic agent according to claim 10, which is an α-amino acid or a derivative thereof represented by the formula: 12. The hypoglycemic agent according to claim 1, wherein the zinc (II) organic complex has a 2-aminothiophenol as a ligand. 13. A 2-aminothiophenol represented by the following general formula (5): (Wherein R ₉ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, or a hetero group which may have a substituent. R 2 represents a cyclic group, and each of R ₉ may be independently two or more on the benzene ring.) Or a derivative thereof. . 14. The hypoglycemic agent according to claim 1, wherein the zinc (II) organic complex has dithiocarbamic acids as ligands. 15. The dithiocarbamic acids are represented by the following general formula (6): (Wherein, R ₁₀ and R ₁₁ each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent.
₁₀ and R ₁₁ may together form an alkylene group which may have a substituent. 15. The hypoglycemic agent according to claim 14, which is dithiocarbamic acid or a derivative thereof represented by the formula: 16. Dithiocarbamic acids are represented by the following general formula (7): (Wherein, R ₁₂ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, or a hetero group which may have a substituent. shows a ring group, hypoglycemic agent of claim 15 said R ₁₂ are each independently may be present 2 or more on the pyrrolidine ring.) pyrrolidine dithiocarbamic acid or its derivative represented by the. 17. The hypoglycemic agent according to claim 1, wherein the zinc (II) organic complex has a ligand having a thiazolidine ring. 18. A ligand having a thiazolidine ring is represented by the following general formula (8): (Wherein, R ₁₃ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, and a hetero group which may have a substituent. A ring group, two of the R ₁₃ may be independently present on the thiazolidine ring, and X ₃ is a lower alkoxy group, an amino group optionally substituted by a lower alkyl group, or a hydroxyl group. , M represents an integer of 0 to 5) .The hypoglycemic agent according to claim 17, which is a carboxylic acid derivative having a thiazolidine ring represented by the formula: 19. The hypoglycemic agent according to claim 1, wherein the zinc (II) organic complex has a ligand having a thiophene ring. 20. A ligand having a thiophene ring is represented by the following general formula (9): (Wherein, R ₁₄ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a halogen atom, a hydroxyl group, an alkoxy group, an amino group which may be substituted, and a hetero group which may have a substituent. A ring group, two or more of the R ₁₄ may be independently present on the thiophene ring, and X ₄ is a lower alkoxy group, an amino group optionally substituted with a lower alkyl group, or a hydroxyl group. And k represents an integer of 0 to 5.)
The hypoglycemic agent according to claim 19, which is a carboxylic acid derivative having a thiophene ring represented by: 21. An organic zinc (II) complex comprising Zn (N ₂ O)
₂ ) type, Zn (O ₄ ) type, Zn (O ₂ S ₂ ) type, Zn
_{(N 2 S} 2) type, or hypoglycemic agent according to any one of claims 1 20 is a Zn _{(S 4)} type of zinc (II) complex. 22. An oral administration preparation comprising a zinc (II) organic complex. 23. The preparation for oral administration according to claim 22, wherein the preparation for oral administration contains a zinc (II) organic complex having an insulin-like action. 24. The oral administration preparation according to claim 22 or 23, wherein the oral administration preparation is a hypoglycemic agent. 25. The oral administration according to any one of claims 22 to 24, wherein the zinc (II) organic complex is a zinc (II) organic complex having a ligand according to any one of claims 3 to 21. Formulation.